Inhibition of the predicted allosteric site of the SARS-CoV-2 main protease through flavonoids

Area of Science:

• Computational drug discovery
• Virology
• Biochemistry

Background:

• The COVID-19 pandemic, caused by SARS-CoV-2, persists despite vaccines due to emerging viral strains.
• The SARS-CoV-2 main protease (Mpro) is a critical viral enzyme and a target for antiviral therapies.
• Viral mutations, particularly in active sites, can reduce the effectiveness of existing treatments and vaccines.

Purpose of the Study:

• To identify and computationally predict novel allosteric inhibitors targeting the SARS-CoV-2 main protease (Mpro).
• To explore the potential of flavonoids as therapeutic agents against SARS-CoV-2.
• To provide a new strategy for developing drugs effective against rapidly mutating SARS-CoV-2 variants.

Main Methods:

• Molecular docking simulations were performed on over 100 distinct flavonoids against the Mpro allosteric site.
• Molecular dynamics simulations were used to assess the stability and interaction of top-hit compounds with Mpro.
• ADMET and Lipinski drug likeness calculations were conducted to evaluate the therapeutic potential of identified inhibitors.

Main Results:

• Four flavonoids—Hesperidin, Schaftoside, Brickellin, and Marein—showed strong binding affinity to the Mpro allosteric site.
• Simulation analyses confirmed sustained interactions between these compounds and the Mpro allosteric region.
• The top four compounds demonstrated favorable ADMET properties, indicating non-toxicity and high intestinal absorption, suggesting significant therapeutic value.

Conclusions:

• Novel allosteric inhibitors of SARS-CoV-2 Mpro were identified using computational methods.
• Flavonoids like Hesperidin, Schaftoside, Brickellin, and Marein represent promising candidates for COVID-19 drug development.
• Targeting the allosteric site of Mpro offers a viable strategy to overcome resistance arising from viral mutations.